Glyceryl trinitrate Macure 1 mg/ml Solution for infusion

- Severe and prolonged ischemic chest pain associated with acute myocardial infarction or unstable angina pectoris.

- Left ventricular cardiac insufficiency and pulmonary congestion associated with myocardial infarction.

- Hypertensive conditions associated with open heart surgery and other surgical procedures.

- Hypertensive crisis with symptoms of cardiac decompensation.

- In surgical procedures, to achieve a controlled hypotension.

Posology

The posology is individual and must be adjusted to suit the patient's needs. The clinical response and haemodynamic variables must be monitored.

Use of Glyceryl Trinitrate Macure solution for infusion requires hospital-like conditions as well as continuous monitoring of the cardiac and circulatory function. Depending on the severity of the patient's condition and the clinical picture of condition, invasive procedures may be indicated in the monitoring of the patient's haemodynamic status, in addition to the normal monitoring (symptoms, blood pressure, pulse, 24-hour urine collection).

In normotensive patients, the systolic blood pressure should not drop more than 10-15 mmHg, in hypotensive patients not more than 5 mmHg, and the pulse rate should not increase more than 5/min unless the clinical picture is clearly improved at the same time.

An intravenous infusion is started at a low rate, 10-20 micrograms/min. The drop rate may be increased according to the response by about 10-20 micrograms/min with 5-10-minute intervals. An effective response is usually achieved at an infusion rate of 50-100 micrograms/min (3–6 mg/h).

Patients with severe anginal symptoms must be treated with a posology of 2–8 mg glyceryl trinitrate/hour (33–133 micrograms/min). The maximum infusion rate can be up to 10 mg/hour. With continuous infusions of high doses, tolerance will develop within 8-24 hours and it may be necessary to increase the dose.

In patients with acute left ventricular failure (pulmonary oedema), the treatment may be initiated, if the blood pressure allows, with an infusion of 1 mg over 3 minutes, followed by a continuous infusion of 2–8 mg/hour for 1–2 days.

To achieve a controlled hypotension during anaesthesia, the dosage is 2–10 micrograms/kg/min, depending on the type of anaesthesia used and the target blood pressure. ECG and invasive blood pressure monitoring is necessary.

The posology of intravenously administered glyceryl trinitrate needs to be adjusted in order to achieve the desired clinical response. Additional adjustments to the intravenous glyceryl trinitrate dosage for patients with severe hepatic or renal insufficiency may be required and these patients may need to be more carefully observed than usual.

Elderly

Adjustment of the dosage is not necessary for elderly patients.

Paediatric population

The safety and efficacy of this medicinal product in children has not yet been established.

Method of Administration

Intravenous use.

Glyceryl Trinitrate Macure solution for infusion may be administered as diluted or undiluted preparation, see section 6.6.

Materials made of polyethylene (PE), polytetrafluorethylene (PTFE) or glass are suitable for infusing Glyceryl Trinitrate Macure. However, use of infusion materials made of polyvinyl chloride (PVC) should be avoided since glyceryl trinitrate binds to PVC.

- Hypersensitivity to the active substance(s), other nitro compounds, or any of the excipients listed in section 6.1

- Acute circulatory failure (shock, collapse)

- Cardiogenic shock (unless a sufficient end-diastolic pressure can be maintained by appropriate measures)

- Severe hypotension (systolic blood pressure less than 90 mmHg)

- Severe hypovolaemia

- Severe anaemia

- Myocardial insufficiency owing to obstruction, aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy or constrictive pericarditis

- Cardiac tamponade

- Conditions associated with an increased intracranial pressure

- During nitrate therapy, phosphodiesterase inhibitors type 5 (PDE5) (e.g., sildenafil, vardenafil, tadalafil) must not be used because PDE5 inhibitors may amplify the vasodilatory effects of glyceryl trinitrate resulting in severe hypotension (see sections 4.4 and 4.5).

Glyceryl Trinitrate Macure must be used with particular caution and under careful medical supervision in patients with:

- low filling pressure (e.g., impaired left ventricular function resulting from acute myocardial infarction). Reducing systolic blood-pressure below 90 mmHg must be avoided.

- Orthostatic dysfunction.

The development of tolerance and cross tolerance to other nitro compounds has been described.

Glyceryl Trinitrate Macure solution must not be used in patients who are taking phosphodiesterase inhibitor-containing products (e.g., sildenafil, vardenafil, tadalafil). Patients who receive medicinal products containing glyceryl trinitrate must be warned not to take phosphodiesterase inhibitor-containing products (e.g., sildenafil, vardenafil, tadalafil) (see sections 4.3 and 4.5).

Hypoxaemia

Caution should be exercised in patients with arterial hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is diminished.

Similarly, caution must be exercised in patients with hypoxaemia and ventilation/perfusion imbalance owing to lung disease or ischaemic heart failure.

Patients with angina pectoris, myocardial infarction or cerebral ischaemia frequently also suffer from abnormalities of the small airways (especially alveolar hypoxia).

Under these circumstances, vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (Euler- Liljestrand mechanism, see also section 4.8). As a potent vasodilator, glyceryl trinitrate could reverse this protective vasoconstriction and, consequently, result in increased perfusion of poorly ventilated areas. This leads to worsening of the ventilation/perfusion imbalance and a further decrease in the partial pressure of arterial oxygen.

Methaemoglobinaemia

Methaemoglobinaemia has been reported after treatment with glyceryl trinitrates. Methaemoglobinaemia must not be treated with methylene blue if the patient has glucose-6-phosphate deficiency or methaemoglobin reductase deficiency (see also section 4.9).

This solution contains 51 mg glucose monohydrate per ml. This should be taken into account in patients with diabetes mellitus.

Concurrent intake of other medicinal products with blood pressure lowering properties, such as beta-blockers, calcium channel antagonists, vasodilators (e.g., PDE5 inhibitors, such as sildenafil), ACE inhibitors, diuretics, etc., and/or alcohol may potentiate the hypotensive effect of glyceryl trinitrate. This might also occur with neuroleptics and tricyclic antidepressants.

The blood pressure lowering effect of Glyceryl Trinitrate Macure will be increased if used together with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil or tadalafil) (see sections 4.3 and 4.4). This may lead to life-threatening cardiovascular complications. Patients who have recently taken phosphodiesterase inhibitors (e.g., sildenafil, vardenafil or tadalafil) must not be treated with Glyceryl Trinitrate Macure.

Reported cases suggest that, when administered concomitantly with dihydroergotamine, glyceryl trinitrate may increase the blood level of dihydroergotamine and its effect. This warrants special attention in patients with coronary artery disease, because dihydroergotamine antagonises the effect of glyceryl trinitrate and may lead to coronary vasoconstriction.

Concurrent administration of glyceryl trinitrate with acetyl salicylic acid may potentiate the blood pressure lowering effects of glyceryl trinitrate.

Non-steroidal anti-inflammatory drugs (except small doses of acetyl salicylic acid as antithrombotic medication) may diminish the therapeutic response to glyceryl trinitrate.

Sapropterin (tetrahydrobiopterin, BH4) is a cofactor of nitric oxide synthase. Caution is advised whenever a medicinal product containing sapropterin is used concomitantly with any substance that expands veins by affecting the metabolism or effect of nitric oxide (NO). Such substances include traditional nitric oxide donors (e.g., glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate, etc.).

If intravenous tissue plasminogen activator (tPA infusion) is administered concomitantly with the glyceryl trinitrate infusion, the plasma clearance of tPA may be accelerated due to increased hepatic blood flow.

The use of heparin and glyceryl trinitrate solution can lead to a partial loss of action of heparin when both medicinal products are given simultaneously by intravenous route.

Fertility

Reproductive toxicity studies performed in rats and rabbits and using different methods of administration did not show any effects on mating, fertility or general reproductive parameters.

There are no data available on the effect of glyceryl trinitrate on fertility in humans.

Pregnancy

Developmental toxicity studies performed in rats and rabbits and using different methods of administration did not reveal any effect on the embryos, foetuses or the young animals even at toxic doses for the dam.

Reproductive toxicity studies performed in rats and rabbits with topically applied glyceryl trinitrate ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively, revealed no evidence of glyceryl trinitrate-induced harm to the foetus. There are, however, no adequate and well-controlled studies in pregnant women.

Since animal studies are not always predictive of human response, glyceryl trinitrate should only be used during pregnancy if clearly necessary, and solely under the direction and continuous supervision of a doctor.

Breastfeeding

Available evidence is inconclusive and inadequate for determining infant risk when used during breastfeeding. According to the data available, nitrates are excreted in breast milk and may cause methaemoglobinaemia in infants. The extent of excretion of glyceryl trinitrate into human breast milk has not been determined. A risk to infants cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to discontinue Glyceryl Trinitrate Macure therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Glyceryl trinitrate may affect the patient's reactivity to an extent that their ability to drive or to operate machinery is impaired. This effect is increased in combination with alcohol.

During administration of glyceryl trinitrate, the following undesirable effects have been observed:

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, pallor and excessive perspiration.

During treatment with glyceryl trinitrate, temporary hypoxaemia may occur, owing to a relative redistribution of the blood flow in hypoventilated alveolar areas.

Particularly in patients with coronary artery disease, this may lead to a myocardial hypoxia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Animal experience

In rats and mice, significant lethality (LD₅₀) was observed at single intravenous doses of 23.2 mg/kg and 10.6 mg/kg, respectively.

In rats and mice, significant lethality (LD₅₀) was observed at single subcutaneous doses of 94 mg/kg and 110 mg/kg, respectively.

Human experience

Symptoms

- fall in blood pressure, below 90 mmHg

- pallor

- sweating

- weak pulse

- reflex tachycardia

- collapse

- syncope

- dizziness postural

- headache

- asthenia

- dizziness

- nausea

- vomiting

- diarrhoea.

Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During glyceryl trinitrate biotransformation, nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of glyceryl trinitrate may cause this adverse reaction.

In very high doses, the intracranial pressure may increase. This may lead to cerebral symptoms.

General procedure

- Stop delivery of the medicine

- General procedures in the event of nitrate-related hypotension:

Special procedures

- raise the blood pressure if very low

- additional administration of vasoconstrictor treatment, such as norepinephrine HCl

- treatment of methaemoglobinaemia

Methaemoglobinaemia must not be treated with methylene blue if the patient has glucose-6-phosphate deficiency or methaemoglobin reductase deficiency (see also section 4.4). When this treatment is contraindicated or ineffective, exchange transfusion and/or transfusion of red cell concentrates is recommended.

- resuscitation measures.

In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.

Pharmacotherapeutic group: Organic nitrates, ATC code: C01DA02.

Glyceryl trinitrate has a direct relaxing effect to vascular smooth muscle, thereby inducing a vasodilatation. At therapeutic doses, the effect is more significant in postcapillary capacitance vessels than in resistance vessels. In the coronary arteries, the vasodilatory effects of glyceryl trinitrate primarily affect large epicardial vessels, whereas the effects on small resistance vessels are limited. This prevents development of steal syndrome. Vasodilatation causes an increase in venous capacity (“pooling”). As a result, venous return to the heart (“preload”) decreases and ventricular volume and filling pressures decrease. Decreased diameter of the ventricle and decreased loading on the venous walls reduce energy consumption and oxygen demand in the heart. Decrease in the internal ventricular pressure facilitates subendocardial circulation in the cardiac wall, improving contractility of the cardiac wall and stroke volume.

Arterial dilatation lowers both the systemic (“afterload”) pressure and the pulmonary circulation pressure.

Glyceryl trinitrate also relaxes the smooth muscle and sphincters in the bronchioles, gastrointestinal tract, ureters, gall bladder, bile duct and oesophagus as well as in the small and large intestine.

At a molecular level, reactive nitric oxide (NO) is formed from nitrates at their site of action. This nitric oxide is identical with the endogenous vasodilator EDRF (“endothelium derived relaxing factor”). NO activates the guanylate cyclase enzyme to produce cyclic GMP, which mediates nitrate-induced relaxation of the smooth muscle.

During the use of Glyceryl Trinitrate Macure, tolerance may develop against the effects alleviating chest pain and against the anti-ischemic effects. Tolerance usually develops if the product is used continuously, and high nitrate doses result in tolerance more rapidly than low doses. Tolerance does not develop in all patients.

General

After administration as an infusion, the effect appears in 1–2 minutes. Distribution volume of glyceryl trinitrate is about 2.1–4.5 l/kg. 60 % of the drug is bound to plasma proteins. The half-life is 2-3 minutes.

Glyceryl trinitrate is mainly metabolised in the liver through a glutathione-dependent organic nitrate reductase. Furthermore, part of the drug is metabolised in the plasma through spontaneous hydrolysis and inorganic degradation. More water soluble, partly or fully denitrated, metabolites are formed as metabolic products that can be further metabolised into glucuronides.

Inorganic nitrites are also formed in the denitration reaction. After glucuronidation, the products are excreted into the urine and bile. There is no enterohepatic circulation. Since the metabolic capacity of organic nitrates is extremely high in the liver, this determines the plasma concentration of nitrates and the duration of the effects.

The pharmacokinetics of glyceryl trinitrate are variable and there is significant interpatient variation. Variation is caused by factors such as a large distribution volume, concentration in the venous walls, substantial differences between arterial and venous concentrations, plasma hydrolysis and wave-like steady-state plasma concentrations. The half-life of 1–3 minutes mainly reflects the alpha distribution phase and the share of hydrolysis in the plasma, since steady-state concentrations or elimination are difficult to monitor.

Properties in patients

Approximately 1 % of the total glyceryl trinitrate amount in the patient can be determined in the plasma. This, as well as the problems in measuring the steady-state concentrations, complicates determination of the concentration/effect ratio.

Elderly patients are more susceptible to the hypotensive effects, especially if they suffer from orthostatic dizziness or stenosis of the carotid arteries.

Prolonged hypotension during the infusion may cause ischemia in organs with angiostenosis.

Patients with a low wedge pressure may be particularly sensitive to hypotensive effects.

Acute toxicity

According to the RTECS*, the LD₅₀ values for glyceryl trinitrate after a single dose are:

*Registry of Toxic Effects of Chemical Substances

Repeated dose toxicity

13 weeks toxicity studies with oral administration and different dosages revealed no toxic effects in:

Methaemoglobinaemia that develops commonly when using organic nitrates occurred occasionally in dogs that were administered 1, 5 and 25 mg/kg orally for 12 months. Toxic effects did not occur when administered intravenously for two weeks with a daily dose of 5 mg/kg for rats and 3 mg/kg for dogs. Two unexplained deaths occurred in the rat group that received a daily dose of 10 mg/kg.

A 26-week study with daily application of 10 percent glyceryl trinitrate to the skin of male rabbits revealed no toxic effects when the dose to the skin was 15 mg/kg/day and to the systemic system 60 mg/kg/day.

Reproductive and Developmental Toxicity

Reproductive and developmental toxicity studies in rats and rabbits using various routes of administration (intravenous, intraperitoneal, transdermal) were conducted. Those studies, comprising tests of fertility, reproductive capacity, embryotoxicity and the peri- and postnatal development, did not reveal any effect on the embryos, foetuses or the young animals even at dosages that were toxic for the dam (5–20 mg/kg). In particular, there were no indications of teratogenic properties of GTN.

In teratology studies in rats and rabbits with topically applied glyceryl trinitrate ointment up to doses of 80 mg/kg/day and 240 mg/kg/day, respectively, no toxic effects on dams and foetuses were seen in any doses tested. Animal teratology studies have not been conducted with glyceryl trinitrate patches.

Mutagenicity

Glyceryl trinitrate has not been extensively examined for mutagenic effects. A gene mutation test in S. typhimurium (Ames-test) revealed a negative result.

Carcinogenicity

No state-of-the-art carcinogenic toxicity studies have been performed to determine the carcinogenic potential of glyceryl trinitrate.

Glucose monohydrate

Water for injections

Hydrochloric acid (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Use of infusion materials made of polyvinyl chloride (PVC) should be avoided since glyceryl trinitrate binds to PVC.

3 years.

After first opening and dilution chemical and physical in-use stability has been demonstrated for 24 hours at 5 ºC and 25 ºC. From a microbiological point of view, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

This medicinal product does not require any special temperature storage conditions. Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Colourless glass vial, closed with bromobutyl rubber stopper with an aluminium cap with a polypropylene disc.

Pack size: 1 x 50 ml and 10 x 50 ml.

Not all pack sizes may be marketed.

The solution for infusion is sterile but not preserved. The vial is not intended for multiple uses. Glyceryl Trinitrate Macure solution for infusion must remain under aseptic conditions as soon as opened.

The medicinal product should be visually inspected prior to use. Only clear solutions free from particles should be used.

Once opened, the medicinal product should be used immediately. Any remaining contents should be discarded.

Glyceryl Trinitrate Macure solution for infusion can be mixed with physiological saline solution, 5–30% glucose solution or Ringer-lactate solution.

Solutions for infusion with a glyceryl trinitrate concentration of 100 micrograms/ml are usually recommended. This is prepared by removing 50 ml of liquid from an infusion bottle of 500 ml and adding one vial (50 ml) of Glyceryl Trinitrate Macure. Higher concentrations may also be used in the solutions, but it is recommended not to exceed the concentration 133 micrograms/ml.

Materials made of polyethylene (PE), polytetrafluorethylene (PTFE) or glass are suitable for infusing Glyceryl Trinitrate Macure. See also sections 4.2 and 6.2.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.